Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer

Nathan F. Schachter, Jessica R. Adams, Patryk Skowron, Katelyn. J. Kozma, Christian A. Lee, Nandini Raghuram, Joanna Yang, Amanda J. Loch, Wei Wang, Aaron Kucharczuk, Katherine L. Wright, Rita M. Quintana, Yeji An, Daniel Dotzko, Jennifer L. Gorman, Daria Wojtal, Juhi S. Shah, Paul Leon-Gomez, Giovanna Pellecchia, Adam J. Dupuy, Charles M. Perou, Ittai Ben-Porath, Rotem Karni, Eldad Zacksenhaus, Jim R. Woodgett, Susan J. Done, Livia Garzia, A. Sorana Morrissy, Jüri Reimand, Michael D. Taylor and Sean E. Egan ()
Additional contact information
Nathan F. Schachter: The Hospital for Sick Children
Jessica R. Adams: The Hospital for Sick Children
Patryk Skowron: The Hospital for Sick Children
Katelyn. J. Kozma: The Hospital for Sick Children
Christian A. Lee: Computational Biology Program, Ontario Institute for Cancer Research
Nandini Raghuram: The Hospital for Sick Children
Joanna Yang: The Hospital for Sick Children
Amanda J. Loch: The Hospital for Sick Children
Wei Wang: The Hospital for Sick Children
Aaron Kucharczuk: The Hospital for Sick Children
Katherine L. Wright: The Hospital for Sick Children
Rita M. Quintana: The Hospital for Sick Children
Yeji An: The Hospital for Sick Children
Daniel Dotzko: The Hospital for Sick Children
Jennifer L. Gorman: Lunenfeld-Tanenbaum Research Institute, Sinai Health System
Daria Wojtal: University of Toronto
Juhi S. Shah: The Hospital for Sick Children
Paul Leon-Gomez: The Hospital for Sick Children
Giovanna Pellecchia: The Center for Applied Genomics, The Hospital for Sick Children
Adam J. Dupuy: Carver College of Medicine, The University of Iowa
Charles M. Perou: University of North Carolina
Ittai Ben-Porath: Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School
Rotem Karni: Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School
Eldad Zacksenhaus: University of Toronto
Jim R. Woodgett: University of Toronto
Susan J. Done: University of Toronto
Livia Garzia: The Hospital for Sick Children
A. Sorana Morrissy: The Hospital for Sick Children
Jüri Reimand: University of Toronto
Michael D. Taylor: The Hospital for Sick Children
Sean E. Egan: The Hospital for Sick Children

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.

Date: 2021
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DOI: 10.1038/s41467-021-25467-w

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